Prostate cancer is prevalent worldwide. Men living in the United States have approximately a 1 in 6 chance of being diagnosed with prostate cancer at some point during their lifetime, and approximately a 1 in 50 chance of dying from prostate cancer (Jemal et al., CA Cancer J. Clin. 59:225-249 (2009), incorporated herein by reference as if set forth in its entirety). The number of men afflicted with prostate cancer is increasing rapidly as the population of males over the age of 50 grows. Thus, strategies for detecting prostate cancer in its early stages are urgently needed.
Conventional prostate cancer screening methods, including digital rectal examination, transrectal ultrasound, and prostate specific antigen (PSA) testing, lack sensitivity and specificity. Elements of PSA screening are controversial: practitioners disagree on the best age for screening, how to interpret elevated PSA values, and how to identify prostate cancers in patients with low serum PSA values. There are also concerns that PSA screening may lead to unnecessary interventions that do not affect long-term outcome and survival (Greene et al., J Urol 182:2232-2241 (2009), incorporated herein by reference as if set forth in its entirety). To overcome the disadvantages of prostate cancer screening methods, researchers have attempted to identify antigens produced by tumor cells that can be utilized as prostate cancer markers. Serum-based screening methods have allowed for rapid identification of many tumor antigens in individuals with many different tumor types (Sahin et al., Proc. Nat. Acad. Sci. 92:11810-11813(1995), incorporated herein by reference as if set forth in its entirety). In fact, serum screening has been so successful that literally hundreds of cancer-associated antigenic proteins have been identified.
Serological identification of antigens by recombinant expression cloning (SEREX) has been used to prioritize potential vaccine targets for prostate cancer. Immunologically recognized proteins of the prostate have been identified by screening sera from: i) individuals with prostate cancer (Dunphy et al., Update Canc. Ther. 22:273-284 (2006); Fossa et al., Br. J. Cancer 83:743-749 (2000); Mooney et al., Int. J. Urol. 13:211-217 (2006)); ii) prostate cancer individuals treated with immune-active therapies (Dunphy et al., J. Immunother. 28:268-275 (2005)); and iii) prostate cancer individuals treated with standard androgen deprivation therapy (Morse and McNeel, Hum. Immunol. 71:496-504 (2010)); each of the foregoing references are herein incorporated by reference as if set forth in their entirety). Sera from individuals with prostate cancer were also used to directly screen a testis tissue cDNA expression library and a panel of defined cancer-testis antigens aberrantly expressed in solid tumors of different histologic types (Hoeppner et al., Cancer Immun. 6:1-7 (2006); Dubovsky and McNeel, Prostate 67:1781-1790 (2007), each incorporated herein by reference as if set forth in its entirety).
Chronic inflammation has been implicated in lung and colon cancers and might similarly promote the development of prostate cancers (Palapattu et al., Carcinogenesis 26:1170-1181 (2005); Narayanan et al., Prostate 69:133-141 (2009); McDowell et al., Prostate 70:377-389 (2010); Dennis et al., Urology 60:78-83 (2002); each incorporated herein by reference as if set forth in its entirety). Tumor-infiltrating lymphocytes are observed in prostate tumor specimens, and chronic inflammatory cells (e.g., lymphocytes and mononuclear cells) are observed adjacent to the earliest premalignant lesions of the prostate (De Marzo et al., Am. J. Pathol. 155:1985-1992 (1999) incorporated by reference herein as if set forth in its entirety). In rodents, chronic prostatitis appears to promote the development of prostate tumors (Gilardoni et al., J. Exp. Clin. Cancer Res. 18:493-504 (1999), incorporated by reference herein as if set forth in its entirety). Human prostate-infiltrating lymphocytes obtained at the time of surgery are oligoclonal suggesting that these lymphocytes recognize tissue-specific antigens (Mercader et al., Proc. Nat. Acad. Sci. 98:14565-14570 (2001); Sfanos et al., Prostate 69:1694-1703 (2009); each incorporated herein by reference as if set forth in its entirety).
While a number of antigens associated with prostate cancer have been identified, it has not yet been determined which of these antigens are predictive of a malignant or premalignant prostate. This is at least in part due to the variation in antibody-antigen profiles of individuals; not every antigen associated with prostate cancer or prostatitis is expressed in every affected individual and not every expressed antigen elicits an immune response in every affected individual. As such, no single antigen can serve as a reliable indicator of prostate cancer or prostatitis. The high level of variation of immunoresponsiveness among individuals has made it difficult to translate antigens associated with prostate cancer into tools useful for predicting prostate cancer, or predicting an increased risk of developing prostate cancer, in populations of men, wherein populations are defined as groups with or without a particular disease or disease stage. Screening men for all antigens that have been associated with prostate cancer is cost-prohibitive and impractical. Thus, there is a need in the art to identify a subset of antigens specific to antibodies associated with pre-malignant and malignant prostate tissue for identifying candidate individuals warranting further prostate examination.